The retinal pigment epithelial (RPE) cell has a major regulatory function in the eye, in a variety of ways influencing the maintenance of retinal integrity and function. In order to study this cell more effectively in vivo and in vitro, we have produced monoclonal antibodies directed against human RPE cells. Using immunoperoxidase assays (ABC), we have identified two mouse IgG monoclonal antibodies that react with the human RPE cell. The monoclonal antibodies are both specific for the RPE cell within the eye because they do not react with any other ocular structures. Moreover, these antibodies do not cross-react with human skin, kidney, or peripheral mononuclear cells. These antibodies recognize cell surface molecules that must be highly conserved, being found in man, monkey, rat, mouse, cow, chicken, and frog. These antibodies, which detect epitopes present solely on RPE cells, provide us with the unique opportunity to evaluate a variety of aspects of RPE cell development and function. Studies of RPE cell development indicate that the epitopes appear only after the cells have begun terminal differentiation. Moreover, these studies indicate that a very specific product of the RPE cell is synthesized as the photoreceptor outer segment starts to develop, suggesting that this product could be involved in an essential step of the outer segment development. Studies on RPE migration also demonstrate the value of these antibodies in evaluating epiretinal membrane formation. These are the first monoclonal antibodies directed solely at the human RPE cell. Further characterization and studies of these antibodies should prove useful in the identification of RPE cells in situ and in vitro. This immunoglobulin will allow us to probe the bioregulatory functions of the cells.